This invention relates to a method for increasing the usefulness, sensitivity and specificity of tests that measure memory and facets of memory, including learning, retention, recall and/or recognition. Specifically, the sensitivity and specificity of such tests are enhanced by selectively weighting the value of specific items recalled by the test subject, either by weighting such items within any specific testing trial or across numerous testing trials. Also disclosed are various methods of reducing ceiling effects in memory tests. The invention also provides improved tests which employ item-specific weighting for the diagnosis of Alzheimer""s Disease and other dementia characterized by memory impairment, as well as a method of screening for and evaluating the efficacy of potential therapeutics directed to the treatment of such dementia.
It is estimated that over the next 20 years, one in every five persons will be over the age of 65. With this new demographic profile will come an increase in a wide variety of age-related conditions, including Alzheimer""s disease (xe2x80x9cADxe2x80x9d) and other forms of dementia. Dementia is a syndrome of progressive decline in multiple domains of cognitive function, eventually leading to an inability to maintain normal social and/or occupational performance. At present, AD is the most common form of dementia, afflicting approximately 4 million Americans. One in ten persons over the age of 65 and nearly half of those over the age of 85 suffer from AD, and AD is the fourth leading cause of death in the U.S. The cost to U.S. society is estimated to be at least $100 billion every year, making AD the third most costly disorder of aging.
Early identification is critical in progressive conditions such as AD, because early treatment may be more effective than later treatment in preserving cognitive function. Furthermore, early detection may allow time to explore options for treatment and care. However, early detection is compromised by the failure of many patients to report early symptoms of AD to their treating physicians, including memory lapses and mild but progressive deterioration of specific cognitive functions, such as language (aphasia), motor skills (apraxia) and perception (agnosia). In addition, studies have documented the difficulty experienced by even well-trained health care professionals in correctly diagnosing AD and other forms of dementia (Callahan, et al., Ann. Intern. Med. 122:422-429, 1995). Accordingly, a simple, sensitive, reliable, and easily administered AD diagnostic test would be of great assistance in targeting individuals for early intervention.
The earliest manifestation of AD is often memory impairment, which is a requirement in each of the two sets of criteria for diagnosis of dementia that are commonly usedxe2x80x94the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer""s Disease and Related Disorders Association (NINCDS/ADRDA) criteria, which are specific for Alzheimer""s disease, and the American Psychiatric Association""s Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, which are applicable for all forms of dementia. Therefore any test for AD or dementia associated with memory impairment should be most sensitive for the early detection of memory impairment. Conventional memory tests are not optimal for the detection of mild dementia or the early stages of Alzheimer""s Disease. Some of these tests are inappropriately sensitive to the patient""s educational level (White and Davis, J. Gen. Intern. Med., 5:438-445, 1990; McDowell and Kristjansson, Mental Status Testing, in Measuring Health: a guide to rating scales and questionnaires, 1996:287-334). They may also fail to test for certain types of memory loss that are typical of early dementia or Alzheimer""s Disease, as well as fail to reflect whether compounds or therapy administered to treat dementia are having the desired effect. These tests also often suffer from a high rate of false negatives (low sensitivity) or false positives (low specificity).
Although there are many variations, a typical memory test is structured as follows. First, the tester presents to the subject a number of items (i.e., bowl, zebra, orange, anger, etc. . . . ) to be recalled from memory. The items may be presented orally, in writing, in pictures, or by any other suitable means. Sometimes the subject is also supplied with a cue associated with each or some of the items on the list. The cue typically is the category that encompasses the associated item or defines an aspect of the associated item, i.e., the cue xe2x80x9canimalxe2x80x9d or xe2x80x9cstripesxe2x80x9d might be presented in association with the item xe2x80x9czebraxe2x80x9d. Certain conventional paired associate tests use unrelated nouns as cues for test items.
The presentation of items in association with a cue, where the subject must first identify the item from the cue, is known as xe2x80x9ccontrolled learningxe2x80x9d. Controlled learning is used in memory tests to assure the attention of the subject and the equal processing of all the items in a list. In addition, it shows that the subjects can identify items from their cues, and induces encoding specificity, by providing cues at the time of encoding information that can later be used to aid recall. The identification of items by matching the items with the associated cues verifies that the required processing was performed by the subject.
In the next step, the subject is asked to recall the items presented to him in the list, either from memory without presentation of the associated cue, known as xe2x80x9cfree recallxe2x80x9d, or after being presented with the associated cue, known as xe2x80x9ccued recall.xe2x80x9d Cued recall may be used selectively to facilitate recall of those items not first recalled by free recall (without any cues).
Variations of memory tests include xe2x80x9ccontrolled rehearsalxe2x80x9d, which refers to a step wherein the subject is instructed to repeat each item as it is presented. Alternately, the subject may be asked to repeat the preceding item as the current item is presented, or the subject may be instructed to repeat both the preceding item and the current item. As with controlled learning, controlled rehearsal assures attention and equal processing of all items, and shows that the required processing was performed.
Some memory tests, particularly tests of delayed recall or forgetfulness, utilize interference delays between memory trials. Interference delays are periods of time between memory trials wherein an unrelated task is performed by the subject to prevent rehearsal by the subject. Common tasks performed to prevent rehearsal include having the subject count, spell, or perform a simple unrelated task.
xe2x80x9cControlled remindingxe2x80x9d refers to a step wherein the subject is reminded of items that were not recalled during each trial. In free recall memory tests, the reminding would not occur until after the subject is given the opportunity to recall as many items as possible. In the case of cued recall, the subject is reminded of the item before the next cue is presented. Controlled reminding may be either xe2x80x9cselective remindingxe2x80x9d, wherein the subject is reminded each time the item is not recalled, or xe2x80x9crestricted remindingxe2x80x9d, wherein the subject is reminded only until the item is recalled once, either with or without presentation of the item. xe2x80x9cContingent learningxe2x80x9d refers to maintaining a constant number of items to be learned. This can be done by adding new items as the old items are learned.
Memory tests known in the art include various combinations of the foregoing elements. For example, the memory component of the Free and Cued Selective Recall Test (xe2x80x9cFCRSTxe2x80x9d) is comprised of an initial controlled learning step, where the patient must first identify items from their associated cues. The patient must then recall sixteen tests items from their associated category cues. Following a brief interference delay, the patient is then asked to recall as many of the presented items as she can by free recall, i.e., without the associated cues, followed by cued recall for items not remembered by free recall. If there are multiple trials, then the subject is selectively reminded (i.e., reminded each time an item is not recalled) of missed items before the next recall trial. The score is the total of uncued responses and cued responses, with each response (whether cued or uncued) worth one point.
Conventional memory tests are scored by tallying the total number of items recalled from a list of items previously presented to the subject, either within any one testing trial or across many testing trials. Each item recalled is accorded the same weight (xe2x80x9cunit countingxe2x80x9d or xe2x80x9cunweighted countingxe2x80x9d), so that a subject recalling items 1 to 5 of a ten item list would be judged to have the same measure of memory as a subject who recalled items 6 to 10 of the same ten item list. Further, a subject recalling items 1 to 5 of a ten item list in a first trial and items 6 to 10 in a second trial would be considered to have the same measure of memory as a subject who recalled items 1 to 5 in the first and second trials, but could not recall items 6 to 10 at all. Memory tests utilizing this type of unweighted counting assume that all the items presented and retrieved are equal in value, i.e., that the probability of encoding, learning, and retaining any single item is equal to the probability of encoding, learning and retaining any other items.
However, items in such a list differ in likelihood of recall, depending on a number of factors. Serial processing at input and output almost always result in xe2x80x9cserial position effectsxe2x80x9d, which are differences in the frequency of recall among list items due to the order in which the items are presented. Simply put, some items are xe2x80x9charderxe2x80x9d or xe2x80x9ceasierxe2x80x9d to recall depending upon the order such items are presented to the subject. These serial position effects are illustrated for groups in serial position curves, which are graphs that show the percentage of subjects recalling the items of a list versus the order in which the items are presented or recalled. These serial position effects show that the probability of recall is affected by the order in which the items are presented (xe2x80x9cpresentation orderxe2x80x9d), or the order in which the items are recalled (xe2x80x9crecall orderxe2x80x9d), or both. Important serial position effects include primacy (higher recall of earlier presented items) and recency (higher recall of the most recently presented items). Analysis of serial position effects is important because the display of certain serial position effects (or the lack thereof) may be associated with dementia. For instance, recall by normal aged subjects is characterized by primacy effects as well as recency effects, but recall by aged subjects with AD is characterized only by recency effects.
Also, unweighted counting ignores qualitative differences in memory impairment, that is, whether impairment in total memory is a result of deficiencies in a particular stage or facet of the memory process, namely a deficiency in encoding information, learning information or retaining information. Such qualitative differences may be essential for the diagnosis of AD or dementia characterized by memory impairment and to appropriately target and evaluate the efficacy of therapeutics directed to the treatment of AD or early dementia.
As a result, measuring memory by unweighted counting (i.e., unit weighting) may not be justified. Although unweighted or unit counting provides a lower bound for memory performance, it sacrifices statistical power by ignoring essential information about the serial position characteristics (probability of retrieval) of retrieved items and about the various processes involved in memory (i.e., encoding, learning and retention). A method of measuring memory that preserves information about the serial position effects of retrieved items or that pinpoints deficiencies in certain elements of total memory would improve the assessment of memory performance, aid in the earlier diagnosis of dementia and AD, and permit sophisticated screening of therapeutics directed to the treatment of AD or dementia.
Essentially all tests of memory, including tests of learning, retention, recall and/or recognition (hereinafter, xe2x80x9cmemory testsxe2x80x9d) involve xe2x80x9cserial processing memoryxe2x80x9d. Serial processing memory refers to the fact that our input and output processing is limited, so that a subject can process only one item at a time during input (i.e., receiving information) and output (i.e., recalling or retrieving information). In this sense, xe2x80x9cmemoryxe2x80x9d comprises units of received information and recalled information. In most tests of serial processing memory, multiple items are presented serially one item at a time to a subject until all the items have been presented (xe2x80x9cserial presentationxe2x80x9d), and the subject reports the remembered items serially one item after another (xe2x80x9cserial recallxe2x80x9d). Items may be presented verbally, visually, or by any other suitable means. However, all memory tests necessarily involve serial processing memory, including but not limited to, tests of narrative recall, biographical or historical recall, or category fluency tests of semantic memory. Therefore, the design and form of memory tests and experiments are limited to serial processing memory tests and experiments that test a subject""s ability to encode, retain and/or retrieve items one at a time as part of a serial collection of items. Further, the encoding, retention and/or retrieval of each item is conditioned by the serial encoding, retention and retrieval of other items that precede and follow each item in presentation and recall.
Not all items presented or retrieved by a subject are equal in value. That is, the probability of encoding, learning and retaining any single item is not necessarily equal to the probability of encoding, learning or retaining any other item, depending upon a wide variety of parameters, including presentation order, recall order, etc. Some items are xe2x80x9charderxe2x80x9d to recall than others, as shown by lower retrieval weights. Furthermore, the frequency and types of items not recalled by a subject can establish memory impairment and may be indicative of AD or other dementias involving memory impairment.
The present invention is directed to various methods of measuring memory in a subject comprising the use of item-specific weighting in the administration and analysis of all types of serial processing memory tests. By recognizing that not all items are of equal value, items may be selectively weighted to amplify and/or pinpoint deficiencies in memory, i.e., deficiencies in First Recall, Learning and Retention. Accordingly, the methods of the present invention improve the assessment of memory performance and aid in the earlier diagnosis of dementia characterized by memory impairment, including but not limited to Alzheimer""s Disease.
One method of the present invention comprises assigning a separate weighted value to each item in a list of items to be recalled from memory based upon the length of retention of the item by the subject before recall (xe2x80x9cRetention Weightingxe2x80x9d). For instance, the present invention provides for the assignment of a separate weighted value for each item in a list of items to be recalled from memory based upon the item""s presentation position (xe2x80x9cPresentation Weightingxe2x80x9d). The items are presented to a subject, and the presentation weighted values of the items actually recalled by the subject are analyzed in order to determine memory impairment. Another method of the present invention comprises presenting to a subject a list of items to be recalled from memory, recording the items actually recalled by the subject, and then assigning a separate weighted value to each item recalled by the subject based upon the item""s recall position (xe2x80x9cRecall Weightingxe2x80x9d). The recall weighted values of items recalled by the subject are then analyzed in order to determine memory impairment. Also provided is a method comprising presenting a list of items to a subject to be recalled from memory, recording items recalled by the subject, and then assigning a separate weighted value to each item recalled by the subject based on the total length of retention of the item by the subject before recall, i.e., retention of the item from presentation to recall (xe2x80x9cTotal Retention Weightingxe2x80x9d). The total retention weighted values of items recalled by the subject then are analyzed in order to determine memory impairment.
The present invention further provides methods for measuring memory in a subject comprising multiple memory trials that use item-specific weighting. In one embodiment of the invention, a list of items to be recalled from memory is presented to a subject and the subject is asked to recall the items presented. Items which are recalled by the subject are recorded, and at least two more memory trials are performed. Separate weighted values are assigned to each item recalled by the subject in each trial, and the assigned weighted values are analyzed to measure the subject""s memory. Although any type of weighting may be used, the value of each item recalled in each trial is preferably weighted according to whether the item had been recalled in the preceding trial or the following trial, i.e., each item is weighted according to its xe2x80x9cRecall Statexe2x80x9d. Another multi-trial memory test of the present invention comprises the steps of, in a first trial, presenting a list of items to a subject to be recalled from memory, and recording items that are recalled by the subject from memory. In a second trial, items not recalled by the subject from memory in the first trial are presented again, and all items recalled by the subject from memory are recorded. More trials may be performed, with or without Selective Reminding (reminding or repeating presentation each time an item is not recalled) or Restricted Reminding (reminding or repeating presentation each time an item is not recalled, but only until initial recall of the item). After the last trial, a separate weighted value is assigned to each item recalled by the subject in each trial, and the weighted values are analyzed in order to determine memory impairment. In a preferred embodiment of the invention, the items are weighted according to whether the item has been recalled in the preceding trial or the following trial and/or according to whether the item was recalled by the subject with or without reminding.
Another method is disclosed for measuring memory in a subject, comprising the steps of serially presenting to a subject a list of items to be recalled from memory, where the items are initially presented together with an associated cue for each item and each cue is a common adjective describing the associated item. The associated cue for each item is then serially presented to the subject so that the subject may recall from memory the associated item from presentation of the relevant cue, however, the cues are serially presented in reverse order than the initial serial presentation order. Items recalled by the subject after presentation of the associated cue are recorded and assigned a separate weighted value, wherein the value for each item is weighted according to the period of retention of the item by the subject before recall. The assigned values of items recalled by the subject can then be analyzed to determine memory impairment.
Also disclosed by the present invention are methods of reducing ceiling effects in serial processing memory tests, comprising introducing a period of extended delay between (a) presentation of a list of items to a subject wherein said items are to be recalled from memory by the subject and (b) first recall of the items by the subject from memory. Alternatively, ceiling effects may be reduced in serial processing memory tests which use free and cued recall by selectively weighting items recalled by the subject by free recall. The results may then be analyzed to establish memory impairment and to determine whether there is indication of dementia characterized by memory impairment or AD.
Further provided is a method of screening agents directed to the treatment or prevention of dementia characterized by memory impairment, including AD, said method comprising comparing a subject""s or a group of subjects"" performance on any of the item-specific weighted memory tests of the present invention before adminstration of the selected agent and after administration of the selected agent to the subject or group of subjects. Alternatively, the results of item-specific weighted memory tests performed by control groups not receiving the selected agent and test groups receiving the selected agent may be compared.
Additionally, the invention provides a method of screening such agents comprising administering any unweighted or unit scored serial processing memory test to members of a control group that have not received the selected agent and to members of a test group that have received the selected agent. Serial position curves using the results of the memory tests are then generated for both the control group and the test group, and the effect of the agent on memory function is determined by comparing the serial position curves of the two groups. Alternatively, the items in the generated serial position curves can themselves be weighted and the the weighted serial position curves of the two groups may be compared. Also disclosed is a method of screening such agents comprising analyzing the serial position curves derived from unweighted serial processing memory tests administered to a subject or a group of subjects before and after treatment of the subject(s) with the agent being screened. The items in the serial position curves may be weighted and the weighted serial position curves can be compared.
It is understood that, in all of the methods of the present invention, assigned values may be analyzed by calculating a score for the subject based on the weighted values of recalled items, and then comparing the score to a reference score. The reference score may establish memory impairment or be indicative of a dementia characterized by memory impairment, including, but not limited to, Alzheimer""s Disease. Further, items may be weighted according to any convenient, useful or desirable parameter, including, but not limited to, retention weighting (presentation weighting, recall weighting and total retention weighting), recall state, normative weighting, amplification weighting, retrieval weighting or weighting based upon serial position effects.
Additional objects and embodiments of the invention will be apparent from the description which follows.